Hepatitis C virus (HCV) infection is the leading cause of liver-related morbidity and mortality in the United States. Although spontaneous clearance of virus occurs in some who are infected and current treatment regimens result in sustained virologic response in others, there remains an unacceptably high frequency of treatment failure. To better understand the contribution of the immune response to viral clearance, we propose the creation of a Bay Area Hepatitis C Cooperative Research Center. The goals of this Center are to define the biology of the innate and adaptive immune responses to HCV in the setting of chronic infection, to understand how these responses are modulated by treatment, and to discern which parameters of the immune response are associated with (and possibly predictive of) an effective antiviral response to therapy. The Center will assemble a strong multidisciplinary team comprised of immunologists and clinical investigators at multiple sites in the San Francisco Bay Area, including three different sites associated with the University of California at San Francisco (UCSF) (San Francisco General Hospital, UC Medical Center, and the San Francisco Veterans Affairs Medical Center) as well as with the California Pacific Medical Center, the Blood Systems Research Institute, and Kaiser Permanente (KP) of Northern California. A Clinical Epidemiology Core (led by Drs. Michele Manos of KP Division of Research and Norah Terrault of UCSF) will develop and manage (a) a retrospective case-control cohort of 200 subjects who did or did not respond to standard-of-care therapy, and (b) a prospective cohort of treatment-naive subjects who will be followed before and after the initiation of therapy. In Project 1 (led by Drs. James Ryan and Lewis Lanier of UCSF), the contribution of innate immunity to treatment response will be studied. Concomitantly, and using the same set of patient samples. Project 2 (led by Drs. Dennis Hartigan- O'Connor and Joseph McCune of UCSF) will analyze the role of adaptive T and B cell responses against HCV. Coordinated analyses of data obtained in both Projects will permit tests of discrete hypotheses that speak to interactions between the innate and adaptive systems. The activities of the Center will be organized through an Administrative Core, directed by the PI (Dr. McCune). We anticipate that the efforts of this Center will provide data that can inform treatment decisions in the short term and contribute to development of better and more generally applicable therapies for chronic HCV disease in the longer term.